This K24 Award application is designed to provide the PI with the time and resources to expand her clinical research efforts and to mentor trainees in this endeavor. In the past decade, Dr. Voskuhl's laboratory has made central findings related to sex hormone treatment in the animal model of multiple sclerosis (MS). Based on these findings, she designed and gained funding for a small pilot clinical trial, then a large multicenter, double-blind, placebo-controlled clinical trial, to treat women with MS using estriol pills. These trials attempt to recapitulate the protective effect of high levels of estriol during late pregnancy, with late pregnancy being a known time of relative protection from MS relapses. Aim 1 will examine immune mechanisms during this multicenter trial by determining whether estriol treatment induces neuroprotective growth factor production by peripheral blood immune cells (PBMCs) derived from subjects in this trial. It will also assess whether estriol treatment decreases matrix metalloproteinases in PBMCs or increases CD4+CD25+ suppressor T cells. Dr. Voskuhl has also just completed a pilot clinical trial in men with MS using treatment with a testosterone gel. This attempts to recapitulate the protective effect of high testosterone levels in young men. Aim 1 will provide the time and resources for the PI to design the follow up, larger, multicenter, double- blind, placebo-controlled clinical trial to treat men with MS using testosterone. It will also use PBMCs available from the recently completed testosterone pilot trial to determine whether testosterone treatment induces neuroprotective growth factor production by PBMCs. In this K24 Award, Dr. Voskuhl will mentor trainees in clinical immunology studies as well as in clinical trial design. Together these studies will assess the efficacy and mechanism of gender tailored sex hormone treatments in MS. If treatment with sex hormones is shown to induce neurotrophic factor production by immune cells, this would have implications for not only for MS, but also for other neurodegenerative diseases. If treatment with sex hormones is shown to down-regulate matrix matalloproteinases and increase CD4+CD25+ suppressor T cells, this would have implications for not only MS, but also for other cell mediated autoimmune diseases.